Beclin-1 and LC3A expression in cutaneous malignant melanomas

Abstract

Autophagy is an intracellular pathway for the degradation of long-lived proteins and damaged organelles. It is, in essence, a recycling process allowing cells to survive oxygen and nutrient depletion. The expression of two autophagy-related proteins, beclin 1 and light chain 3A (LC3A) was investigated in 79 nodular cutaneous melanomas. The results were correlated with histopathological factors, vascular density, and hypoxia-related proteins [hypoxia-inducible factors (HIF1α and HIF2α) and lactate dehydrogenase 5]. The reactivity of both autophagy-related proteins was uniformly cytoplasmically diffused. High beclin 1 and LC3A reactivity was related to tumor hypoxia, as this was inferred from the intense expression of HIF1α and lactate dehydrogenase 5, whereas low beclin 1 and LC3A expression was linked with an increased vascular density. In addition, beclin 1 was related to disease-specific survival which, however, exposed a biphasic pattern. A strong beclin 1 expression extending over a tumor area of more than 50% (high) was associated with an increased rate of early deaths, whereas a similarly strong, but less-extensive cytoplasmic reactivity (<10% tumor area; low) defined a sharp fall in the survival 5 years after surgery. Furthermore, the low beclin 1 expression was associated with high Breslow's depth, high Clark's level, and ulceration. Low LC3A expression was also related to ulceration, but not to other histopathological features nor prognosis. In multivariate analysis, beclin 1 was an independent prognostic variable. It is concluded that extensive autophagic activity is generated by tumor hypoxia and anaerobic glycolysis, whereas angiogenesis maintains low autophagic activity. Atg6/beclin 1 was proved to be capable of deciphering the prognosis in cutaneous malignant melanoma, but the matter requires further investigation.

Autophagy Is a Protective Mechanism for Human Melanoma Cells under Acidic Stress

“…Moreover, high basal autophagy is required for growth of pancreatic cancer and human cancers carrying activated K-RAS (36,64). Intriguingly, up-regulated autophagy linked to hypoxia and acidity has been reported as a marker of poor prognosis in melanoma and colorectal cancer (39,40). In line with this, autophagy was shown to be mostly localized in hypoxic nonvascularized tumor regions (63), suggesting that autophagy may be important to sustain tumor growth and survival in the developing, scarcely perfused tumors.…”

Expression and clinical significance of Beclin-1 in gastric cancer tissues of various clinical stages

“…The Beclin-1 gene is located on chromosome 17q21, which is frequently deleted in breast, ovarian and prostate cancer (23). Furthermore, Beclin-1 +/-mutant mice demonstrate a particularly high incidence of tumors, indicating that Beclin-1 may potentially be a haploinsufficient tumor suppressor (24)(25)(26). Thus, in the present study, the expression of Beclin-1 was evaluated in human gastric cancer specimens and cell lines.…”

“…During the progression of cancer, cancer cells gradually acquire the capacity to evade cell death. Autophagy is an important type of cell death in tumors (23)(24)(25)(26) and Beclin-1 may contribute to its induction. However, although in the early stages, Beclin-1 was strongly expressed in gastric cancer tissues, such changes were not observed in late-stage gastric cancer specimens (TNM stage Ⅲ).…”

Sonic Hedgehog in cancer stem cells: a novel link with autophagy

“…It has been observed that extensive autophagy is generated by tumor hypoxia and anaerobic glycolysis, whereas angiogenesis maintains low autophagic activity. In fact, autophagy localizes to hypoxic regions of tumors most distal to blood vessels where is supports tumor cell survival (Sivridis et al, 2011).…”